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L0301P63 - Action Potential and Propagating the Action Potential
Resting Membrane Potential *negative set by intracellular anions trapped within the cell (chaperoning large proteins) *potential value set by relative permeability of Na+ and K+ Ion Channels K+ Channels *K2P Channels **at rest **15 members of the family *Kv **during activity **40 members of the family Na+ Channels *Nav **during activity **9 members of the family Ca2+ Channels *Ca2+v **during transmitter released (and other functions) Channels in Depth K2P Channels *two-pore (domain) potassium channels **made of four transmembrane segments *fundamental resting membrane K channels in all cells *activated only by basic pH **cannot really be manipulated otherwise In medicine: *volatile anaesthetics increase activity of K2P **Vm becomes more negative - closer to Nernst potential of K+ **closes down activity within cells *found in sensory neuron and is currently being investigated as a therapeutic option to treat chronic pain *suppressed in hypoxia and epilepsy **allows cells to become more excitable *involved in polycystic kidney disease Voltage Gated Sodium (NaV) Channels *very large protein with four pore domains with 6 transmembrane segments *essential in neurons *Nernst potential = ENa = +64mV *activated by depolarisation **i.e. Vm determines if they are opened **may not activate with every stimulus - “miss” or “failure” **speed of response to stimulus may vary **maximum one response per stimulus ***limits the Na+ in the cell *open momentarily when activated - “flicker” **∴ no flickering when channel is closed *activation - all-or-nothing snowball effect: **membrane becomes positive in one area, local NaV open which in turn stimulates other NaVs to open Inactivated State of NaV Function of inactivation: *ensure that the response is brief *prevents excessive ion entry *saves energy, while getting the job done *membrane must remain nicely negative at reset, otherwise it remains inactivated Rest vs Activity At rest: *K2P channels open *NaV channels closed *pK dominates *∴ Vm = -70mV During activity: *same number of K2P channels open *many NaV channels flicker open *increase in pNa *∴ Vm = +40mV (large depolarisation) NaV during Action Potential (AP) *Na+ enters the cell (neuron) via a few Na+ channels at first *initial slow depolarisation **induces the opening of additional Na+ *reaches a threshold **positive feedback, “snowball” effect *very rapid depolarisation - overshoots 0mV **very fast (as there are lots of channels) **very brief (~2ms) ***channels go into inactivated state *all-or-nothing: unstoppable once threshold is reached *NaV becomes blocked when stung by a blue-ringed octopus, puffer fish or blue-green algal toxins Termination of the AP *occurs when the channels go into inactivated state *pNa will return to its low value *∴Vm returns to resting membrane potential Failure of Inactivation: Hyper-excitability *some neonatal and infant forms of epilepsy **mutations at various loci (chromosomes 9 and 20) **one on S4 *inactivation incomplete (red) Voltage Gated Potassium (Kv) Channels *activated by large depolarisation *each subunit has 1 pore domain with 6 transmembrane segments *four subunits join to form the full conducting ion channel *Nernst potential = EK = -90mV Kv during Action Potential *depolarisation: membrane potential changes drastically activating Kv *response is not instantaneous (takes ~1ms), however they continue flickering as long as the stimulus is continually provided **i.e. does not go into inactivation state *creates an outward current to rectify the membrane potential **also called the delayed rectifier (KDR) *can be blocked by 4-aminopyridine *inward current - Na+ moving into the cell *outward current - K+ moving out the cell The Action Potential *depolarisation activates opening NaV *upstroke activates opening of KDR (Kv) *shortens AP duration *reduces amplitude *induced after hyper-polarisation **suppresses excitability **speeds recovery of Na+ channels *Na+/K+ ATPase “cleans up” after **restores ion levels **takes time *graph: line goes below RMP due to combined effect of K2P and Kv Action Potential Summary 1. Overshoot *the other side of 0mV *fails to reach +64mV due to inactivation of the Na+ channels 2. Threshold *when the inward Na+ exceeds resting outward *K+ current (snowball effect kicks in) 3. Return to RMP *rapid inactivation of Na+ channels Definitions Threshold *the membrane potential at which enough NaV open so that the permeability (p) of the membrane favours Na over K Rising Phase *when the inside of the membrane has a negative electrical potential **large driving force on Na+ ions *Na+ ions rush into the cell through NaV causing rapid depolarisation Overshoot *because the relative permeability favours Na, Vm goes to a value close to ENa which is greater than 0mV Falling Phase *NaV inactivate and Kv activate *great driving force on K+, causing them to move out of the cell and Vm to become negative again Undershoot *open Kv add to resting K membrane permeability, and very little Na permeability causing hyper-polarisation Absolute Refractory Period *another action potential cannot be activated until Vm goes sufficiently negative to  de-inactivate the NaV channels Summary